title: The sphingolipid degradation product trans-2-hexadecenal induces cytoskeletal reorganization and apoptosis in a JNK-dependent manner.
abstract: The bioactive signaling molecule D-erythro-sphingosine-1-phosphate (S1P) is irreversibly degraded by the enzyme S1P lyase (SPL). The reaction of SPL with C18-S1P generates ethanolamine phosphate and a long-chain fatty aldehyde, trans-2-hexadecenal. Modulation of SPL expression in cells and organisms produces significant phenotypes, most of which have been attributed to corresponding changes in S1P-dependent signaling. However, the physiological functions of SPL products are not well understood. In the present study, we explored the biological activities of trans-2-hexadecenal in human and murine cells. We demonstrate that trans-2-hexadecenal causes cytoskeletal reorganization leading to cell rounding, detachment and eventual cell death by apoptosis in multiple cell types, including HEK293T, NIH3T3 and HeLa cells. Trans-2-hexadecenal stimulated a signaling pathway involving MLK3 and the respective phosphorylation of MKK4/7 and JNK, whereas ERK, AKT and p38 were unaffected. Trans-2-hexadecenal-induced apoptosis was accompanied by activation of downstream targets of JNK including c-Jun phosphorylation, cytochrome c release, Bax activation, Bid cleavage and increased translocation of Bim into mitochondria. The antioxidant N-acetylcysteine prevented JNK activation by trans-2-hexadecenal. Further, inhibition of JNK abrogated the cytoskeletal changes and apoptosis caused by trans-2-hexadecenal, whereas Rac1 and RhoA were not involved. In conclusion, our studies provide a new paradigm of sphingolipid signaling by demonstrating for the first time that S1P metabolism generates a bioactive product that induces cellular effects through oxidant stress-dependent MAP kinase cell signaling.
authors.affiliation: Center for Cancer Research, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA. akumar@chori.org
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Hoe-Sup
authors.initials: HS
authors.lastname: Byun
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.forename: Julie D
authors.initials: JD
authors.lastname: Saba
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000447:Aldehydes / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D003599:Cytoskeleton / Q000378:metabolism*; D004789:Enzyme Activation; D016166:Free Radical Scavengers / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D041681:NIH 3T3 Cells; D010590:Phalloidine / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D000111:Acetylcysteine; D000447:Aldehydes; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; D016166:Free Radical Scavengers; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D010590:Phalloidine; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D013107:Sphingolipids; D051028:bcl-2-Associated X Protein; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C494826:BAX protein, human; C000606775:BCL2L11 protein, human; C494814:BID protein, human; C000606776:Bcl2l11 protein, mouse; C107953:RAC1 protein, human; C519712:2-hexadecenal